Structural basis for recognition of 53BP1 tandem Tudor domain by TIRR

Nature Communications
Yaxin DaiZheng Zhou

Abstract

P53-binding protein 1 (53BP1) regulates the double-strand break (DSB) repair pathway choice. A recently identified 53BP1-binding protein Tudor-interacting repair regulator (TIRR) modulates the access of 53BP1 to DSBs by masking the H4K20me2 binding surface on 53BP1, but the underlying mechanism remains unclear. Here we report the 1.76-Å crystal structure of TIRR in complex with 53BP1 tandem Tudor domain. We demonstrate that the N-terminal region (residues 10-24) and the L8-loop of TIRR interact with 53BP1 Tudor through three loops (L1, L3, and L1'). TIRR recognition blocks H4K20me2 binding to 53BP1 Tudor and modulates 53BP1 functions in vivo. Structure comparisons identify a TIRR histidine (H106) that is absent from the TIRR homolog Nudt16, but essential for 53BP1 Tudor binding. Remarkably, mutations mimicking TIRR binding modules restore the disrupted binding of Nudt16-53BP1 Tudor. Our studies elucidate the mechanism by which TIRR recognizes 53BP1 Tudor and functions as a cellular inhibitor of the histone methyl-lysine readers.

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Citations

Sep 28, 2018·Nucleic Acids Research·Rosario AvolioDanilo S Matassa
Feb 28, 2019·Nucleic Acids Research·Naike Salvador MorenoPierre-Alexandre Vidi
Jul 25, 2018·Nature Structural & Molecular Biology·Yi Zhang, Tatiana G Kutateladze
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May 21, 2020·Nucleic Acids Research·Sunny SharmaMegerditch Kiledjian
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May 2, 2020·Signal Transduction and Targeted Therapy·Rui-Xue Huang, Ping-Kun Zhou
Aug 9, 2020·Nature Reviews. Genetics·Dali ZongAndré Nussenzweig
Jan 14, 2021·The Biochemical Journal·Rashmi Panigrahi, J N Mark Glover
Jan 16, 2021·Journal of Zhejiang University. Science. B·Fan Zhang, Zihua Gong
Jan 28, 2021·Cancers·Danielle P JohnsonSrividya Bhaskara
Feb 12, 2021·Bioorganic & Medicinal Chemistry·Yanli SunShijie Chen
May 8, 2021·Molecular Cell·Nishita ParnandiDipanjan Chowdhury
Jul 1, 2021·Cell Reports·Janna LuessingNoel Francis Lowndes

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Methods Mentioned

BETA
acetylation
pull-down
pull down
isothermal titration calorimetry
NMR
PCR

Software Mentioned

PROCHECK
PHENIX
PyMOL
PHASER
PISA
Sedfit
HKL2000
Origin
Quantity One
COOT

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